AbstractComplement component 3a (C3a) plays a crucial role in the immune response and host defense, but it is also involved in pro‐inflammatory responses, causing many inflammatory disorders. Blockade of C3a has been regarded as a potent therapeutic strategy for inflammatory diseases. Here, we present the development of a human C3a (hC3a)‐specific protein binder, which effectively inhibits pro‐inflammatory responses. The protein binder, which is composed of leucine‐rich repeat modules, was selected against hC3a through phage display, and its binding affinity was matured up to 600 pM by further expanding the binding interface in a module‐by‐module manner. The developed protein binder was shown to have more than 10‐fold higher specificity to hC3a compared with human C5a, exhibiting a remarkable suppression effect on pro‐inflammatory response in monocyte, by blocking the interaction between hC3a and its receptor. The hC3a‐specific protein binder is likely to have a therapeutic potential for C3a‐mediated inflammatory diseases.